TNF expression of macrophages is under stringent translational control that depends on the p38 MAPK/MK2 pathway and the AU–rich element (ARE) in the TNF mRNA. Here, we elucidate the molecular mechanism of phosphorylation-regulated translation of TNF. We demonstrate that translation of the TNF-precursor at the ER requires expression of the ARE–binding and -stabilizing factor human antigen R (HuR) together with either activity of the p38 MAPK/MK2 pathway or the absence of the ARE-binding and -destabilizing factor tristetraprolin (TTP). We show that phosphorylation of TTP by MK2 decreases its affinity to the ARE, inhibits its ability to replace HuR, and permits HuR-mediated initiation of translation of TNF mRNA. Since translation of TTP's own mRNA is also regulated by this mechanism, an intrinsic feedback control of the inflammatory response is ensured. The phosphorylation-regulated TTP/HuR exchange at target mRNAs provides a reversible switch between unstable/non-translatable and stable/efficiently translated mRNAs.
Autophagy is a tightly regulated catabolic process wherein cells under stress sequester cytosolic constituents like damaged proteins and organelles in double-membrane vesicles called autophagosomes. The autophagosomes degrade their cargo by lysosomal proteolysis generating raw materials for the biosynthesis of vital macromolecules. One of the initial steps in the assembly of autophagosomes from pre-autophagic structures is the recruitment and activation of the class III phosphatidylinositol 3-kinase complex consisting of Beclin 1 (BECN1), VPS34, VPS15, and ATG14 proteins. Several pieces of evidence indicate that the phosphorylation and ubiquitination of BECN1 at an array of residues fine-tune the responses to diverse autophagy modulating stimuli and helps in maintaining the balance between pro-survival autophagy and pro-apoptotic responses. In this mini-review, we will discuss the importance of distinct BECN1 phosphorylation events, the diverse signaling pathways and kinases involved and their role in the regulation of autophagy.
Metastasis is a multistep process that involves the dissemination of cells from the primary tumor and colonization of distant secondary organs. Epithelial cells at the invasive front of a carcinoma acquire an enhanced migratory phenotype in a process called epithelial-to-mesenchymal transition (EMT). This cellular plasticity seems to drive the initiation of metastasis. Identifying important molecules and understanding their molecular mechanisms is a key to cancer prognosis and the development of therapeutics for late stage malignancies. Recent advances in sequencing technology uncovered that the mammalian genome is pervasively transcribed into many nonprotein-coding RNAs including the class of long noncoding RNA, a.k.a. lncRNA. Several lncRNAs are differentially expressed in carcinomas and they are emerging as potent regulators of tumor progression and metastasis. Here, we review the diverse molecular mechanisms, cellular roles and regulatory patterns that are becoming apparent for the noncoding transcriptome. Chromatin modification, epigenetic regulation, alternative splicing and translational control by MALAT1, HOTAIR and TRE lncRNAs represent important examples of lncRNA-mediated control of cell migration and invasion, EMT and metastasis. Beyond these better characterized examples, numerous additional transcripts have been associated with cancer metastasis, but their functional roles await their discovery.Metastasis is a key process in cancer progression, wherein cells in a primary tumor acquire invasive properties and disseminate to other sites in the body to initiate secondary lesions. 1 This complex process involves most of the transdifferentiation steps unique to embryonic development. While aberrant proliferation is a necessity for tumor initiation, a second hit which changes the migratory properties and cell-cell contacts is crucial for the spread of tumor cells in the body. 2 Epithelial-to-mesenchymal transition (EMT) is a key step by which epithelium-derived cancer cells lose their intercellular contacts, upregulate components of the contractile cytoskeleton and move out of the benign primary tumor. 3,4 On the contrary, a reverse of this process (MET) is required for migrating cells to colonize a secondary site. In addition, effective metastasis requires suppression of anoikis and upregulation of multiple matrix degrading enzymes. 2,5 A complex interplay of signals regulate these processes in ways unique to different types of cancers 6 and identification of novel players in the process of tumor dissemination is crucial for cancer prognosis and the development of therapeutics for late stage malignancies. While the majority of these studies focus on protein effectors of metastasis, the importance of noncoding RNAs is now being appreciated. 7 LncRNAs are generally defined as RNA transcripts longer than 200 nucleotides (nt) with no protein-coding potential. Recent advances in sequencing technologies have revealed that the human genome is pervasively transcribed while only <2% transcripts code for proteins...
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